2. Academic Validation
  3. A Versatile Bioorthogonal Theranostic Platform Enables Relay Activation of Tumor Cell Imaging and Targeted Protein Degradation

A Versatile Bioorthogonal Theranostic Platform Enables Relay Activation of Tumor Cell Imaging and Targeted Protein Degradation

  • J Am Chem Soc. 2025 Nov 27. doi: 10.1021/jacs.5c11564.
Feilong Sun 1,  Tian Wang 2,  Pengfei Wang 3 4,  Jiaxin Shi 2,  Yanyan Shen 3,  Guilong Wang 5,  Biyu Yang 3,  Huiwen Li 1 4,  Qiumeng Zhang 1,  Yi Chen 3 4,  Xuan Zhang 1 2 4
Affiliations

Affiliations

  • 1 Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 41311144 DOI: 10.1021/jacs.5c11564
Abstract

Targeted protein degradation offers therapeutic promise but often suffers from on-target off-tissue toxicities. To overcome this challenge, we developed a versatile theranostic platform that integrates tumor cell imaging with precisely controlled protein degradation. Central to this platform is XZ2223, a glutathione (GSH)-cleavable bioorthogonal trigger that couples Cancer cell labeling with concomitant tetrazine release, thereby activating trans-cyclooctene (TCO)-caged CRBN-recruiting degrader prodrugs, Pro-CC-885 and Pro-dBET6, to induce on-demand degradation of GSPT1 and BET, respectively. Coadministration of XZ2223 with either prodrug afforded robust tumor imaging and efficient protein degradation in xenograft models, while the XZ2223/Pro-dBET6 combination further elicited in vivo antitumor efficacy with reduced systemic toxicity. This innovative platform shows potential as a dual-function approach for precision Cancer therapy.

Figures
Products